Most breast cancers, have increased levels of the tyrosine kinase Src, which has been postulated to promote oncogenic signaling by both growth factor and hormone receptors, as well as to facilitate both survival and invasive behavior. In addition, inhibition of Src has been proposed as a mechanism to restore sensitivity to trastuzumab (in the case of Her2 positive tumors) and tamoxifen (in the case of ER/PR+ tumors). Yet clinical trials in breast cancer with multi-targeted kinase inhibitors that inhibit Src (dasatinib, bosutinib and saracatinib) have yet to meet with great success. For example, a recent phase II trial of dasatinib in progressive advanced breast cancer showed disease control in 19% of patients with ER/PR+ tumors, with no responses noted in Her2+ or triple negative tumors. One notable difference between ER+ and other breast cancers is that p53 mutation is much less common in the former than the latter. It is also known that loss of p53 function leads to a worse outcome in breast cancer. Using mesenchymal cells as a model system, we have previously shown that Src family kinases (SFKs) are required for mitogenesis elicited by a variety of growth factors, including PDGF and EGF. In addition, we have determined that SFKs are required to overcome a cell cycle block controlled by p53: if p53 is absent or mutated, SFKs are no longer necessary for mitogenic signaling. We have confirmed a requirement for SFKs for G1>S progression of breast cancer cells in response to estrogen. We hypothesize that Src is required for tumor cell growth only in those breast cancers with functional p53, and predict that p53 status will dictate how breast cancers will respond to Src inhibitors. The outline of our hypothesis is shown in the schematic. Here we will focus on the effects of ER-activated Src, and for this proposal, not evaluate the genomic and transcription factor crosstalk effects of the estrogen receptor. To test our hypothesis, we will determine the effect of p53 status on the response of ER+ve tumor cells to Src inhibitors, and evaluate the effect of Src inhibition on signaling events downstream of ER. There are several innovative aspects to this proposal, including the first demonstration that p53 status can affect SFK-dependent cell cycle progression of a human cancer cell, and the use of the understudied SFK inhibitor SU11333 both in vitro and in vivo. The outcome of this research will be a more complete understanding of the role of Src in ER+ve breast cancer progression, and how p53 status might affect this. This would set the stage for more in depth analyses of the signaling pathways involved. Furthermore, if our hypothesis is correct, this would have potential clinical impact, and might justify the continued testing of Src inhibitors in ER+ve breast cancer. More broadly, the data might also justify determining p53 status during enrollment in Src inhibitor studies in other cancer types.